JP6433513B2 - Porous hollow fiber filtration membrane - Google Patents
Porous hollow fiber filtration membrane Download PDFInfo
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- JP6433513B2 JP6433513B2 JP2016570659A JP2016570659A JP6433513B2 JP 6433513 B2 JP6433513 B2 JP 6433513B2 JP 2016570659 A JP2016570659 A JP 2016570659A JP 2016570659 A JP2016570659 A JP 2016570659A JP 6433513 B2 JP6433513 B2 JP 6433513B2
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- 239000012528 membrane Substances 0.000 title claims description 165
- 239000012510 hollow fiber Substances 0.000 title claims description 99
- 238000001914 filtration Methods 0.000 title claims description 90
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 85
- 239000011148 porous material Substances 0.000 claims description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- 241000700605 Viruses Species 0.000 claims description 53
- 102000004169 proteins and genes Human genes 0.000 claims description 41
- 108090000623 proteins and genes Proteins 0.000 claims description 41
- 229920000642 polymer Polymers 0.000 claims description 39
- 229920002492 poly(sulfone) Polymers 0.000 claims description 35
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 16
- 239000012460 protein solution Substances 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 11
- 239000004695 Polyether sulfone Substances 0.000 claims description 7
- 229920006393 polyether sulfone Polymers 0.000 claims description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 48
- 238000005345 coagulation Methods 0.000 description 41
- 230000015271 coagulation Effects 0.000 description 41
- 239000002904 solvent Substances 0.000 description 35
- 239000011550 stock solution Substances 0.000 description 33
- 239000007788 liquid Substances 0.000 description 26
- 238000001179 sorption measurement Methods 0.000 description 23
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 23
- 238000000034 method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- 230000004907 flux Effects 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 13
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- 238000009987 spinning Methods 0.000 description 12
- 230000007423 decrease Effects 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000702619 Porcine parvovirus Species 0.000 description 6
- 229960000074 biopharmaceutical Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 241000125945 Protoparvovirus Species 0.000 description 5
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 5
- -1 diol compound Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000007711 solidification Methods 0.000 description 5
- 230000008023 solidification Effects 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 230000001112 coagulating effect Effects 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000007847 structural defect Effects 0.000 description 4
- 239000011800 void material Substances 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 230000000415 inactivating effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 238000010335 hydrothermal treatment Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 238000007602 hot air drying Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 230000036619 pore blockages Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000009849 vacuum degassing Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
- B01D71/68—Polysulfones; Polyethersulfones
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/022—Artificial gland structures using bioreactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/02—Hydrophilization
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/218—Additive materials
- B01D2323/2182—Organic additives
- B01D2323/21839—Polymeric additives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/218—Additive materials
- B01D2323/2182—Organic additives
- B01D2323/21839—Polymeric additives
- B01D2323/2187—Polyvinylpyrolidone
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/022—Asymmetric membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/022—Asymmetric membranes
- B01D2325/0231—Dense layers being placed on the outer side of the cross-section
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/04—Characteristic thickness
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/36—Hydrophilic membranes
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Analytical Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Water Supply & Treatment (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Description
本発明は、多孔質中空糸濾過膜に関する。 The present invention relates to a porous hollow fiber filtration membrane.
近年、副作用が少ないことや治療効果が高いことにより、血漿分画製剤やバイオ医薬品を用いた治療が広まってきている。しかし、血漿分画性製剤はヒト血液由来であることから、バイオ医薬品は動物細胞由来であることから、ウイルス等の病原性物質が混入する可能性があり、混入する可能性のある病原性物質を処理する工程を含まずに製造した血漿分画製剤やバイオ医薬品を患者等に投与するとウイルスに感染するリスクがある。
血漿分画製剤やバイオ医薬品の精製工程において、ウイルス感染に対する安全性を付加する技術が用いられている。
安全性を付加する技術として、ウイルスを不活化する方法及びウイルスを除去する方法が挙げられる。In recent years, treatments using plasma fractionated preparations and biopharmaceuticals have become widespread due to low side effects and high therapeutic effects. However, since the plasma fractionation product is derived from human blood and the biopharmaceutical is derived from animal cells, pathogenic substances such as viruses may be mixed. There is a risk of infection with a virus when a plasma fraction preparation or a biopharmaceutical produced without including the step of treating is administered to a patient or the like.
In the purification process of plasma fractionation preparations and biopharmaceuticals, techniques for adding safety against virus infection are used.
Examples of techniques for adding safety include a method for inactivating viruses and a method for removing viruses.
ウイルスを不活化する方法として、加熱処理、光学的処理、及び化学薬品処理等が挙げられ、ウイルスを除去する方法として、膜濾過法が挙げられる。
近年、ウイルスを不活化する方法における、タンパク質の変性、不活化効率、及び薬品の混入等の問題から、ウイルスの熱的及び化学的な性質にかかわらず、すべてのウイルスに有効な膜濾過法が広まっている。Examples of methods for inactivating viruses include heat treatment, optical treatment, and chemical treatment, and examples of methods for removing viruses include membrane filtration.
In recent years, due to problems such as protein denaturation, inactivation efficiency, and chemical contamination in methods of inactivating viruses, membrane filtration methods effective for all viruses have been developed regardless of the thermal and chemical properties of viruses. It is widespread.
ウイルスの種類としては、小さいウイルスとして、直径１８〜２４ｎｍのパルボウイルスや直径２５〜３０ｎｍのポリオウイルスがあり、比較的大きいものでは直径８０〜１００ｎｍのＨＩＶウイルスがある。近年、パルボウイルス等の小さいウイルス除去に対するニーズが特に高まっている。 As types of viruses, small viruses include parvoviruses having a diameter of 18 to 24 nm and polioviruses having a diameter of 25 to 30 nm, and relatively large viruses include HIV viruses having a diameter of 80 to 100 nm. In recent years, the need for removal of small viruses such as parvovirus has been particularly increased.
精製工程に使用されるウイルス除去膜に求められる第一の性能は、安全性である。安全性とは、血漿分画製剤やバイオ医薬品にウイルス等の病原性物質を混入させないことである。
ウイルス除去膜に求められる第二の性能は、生産性である。生産性とは、５ｎｍサイズのアルブミンや１０ｎｍサイズのグロブリン等のタンパク質を効率的に回収することである。
生産性の観点から、孔径が数ｎｍ程度の限外濾過膜及び血液透析膜、並びにさらに小孔径の逆浸透膜は、濾過時にタンパク質が孔を閉塞させ、濾過中にＦｌｕｘが低下し、タンパク質の回収効率が低下するため、ウイルス除去膜として適していない。また、パルボウイルス等の小さいウイルス除去を目的とした場合、ウイルスのサイズとタンパク質のサイズが近いため、上記の安全性と生産性を両立させる高度な技術が要求される。加えて、濾過中のＦｌｕｘ低下の原因は、サイズ因による孔の閉塞だけではなく、タンパク質の孔表面への吸着による孔の閉塞もある。
したがって、ウイルス除去膜は、孔径の精密な設計だけではなく、孔表面の設計も重要となる。The first performance required for the virus removal membrane used in the purification process is safety. “Safety” means that a pathogenic substance such as a virus is not mixed in a plasma fractionation preparation or a biopharmaceutical.
The second performance required for the virus removal membrane is productivity. Productivity is the efficient recovery of proteins such as 5 nm albumin and 10 nm globulin.
From the viewpoint of productivity, ultrafiltration membranes and hemodialysis membranes having a pore size of several nanometers, and reverse osmosis membranes having a smaller pore size, block the pores during filtration and reduce the flux during filtration. Since the recovery efficiency decreases, it is not suitable as a virus removal membrane. Moreover, when aiming at the removal of small viruses such as parvovirus, since the size of the virus is close to the size of the protein, an advanced technique that achieves both the above safety and productivity is required. In addition, the cause of the decrease in flux during filtration is not only pore clogging due to size, but also pore clogging due to protein adsorption on the pore surface.
Therefore, in the virus removal membrane, not only the precise design of the pore diameter but also the design of the pore surface is important.
特許文献１には、ポリスルホン系高分子とビニルピロリドンと酢酸ビニルの共重合体のブレンド状態から製膜されたウイルス除去膜が開示され、親水性高分子であるビニルピロリドンと酢酸ビニルの共重合体が膜厚方向で均一に分散していることを、外表面近傍と膜全体の親水性高分子の含有率測定により評価している。
特許文献２には、ポリスルホン系高分子とビニルピロリドンと酢酸ビニルの共重合体のブレンド膜に多糖類誘導体がコーティングされたウイルス除去膜が開示されている。Patent Document 1 discloses a virus removal membrane formed from a blend of a polysulfone polymer, a copolymer of vinylpyrrolidone and vinyl acetate, and a copolymer of vinylpyrrolidone and vinyl acetate which is a hydrophilic polymer. Is uniformly dispersed in the film thickness direction by evaluating the content of the hydrophilic polymer in the vicinity of the outer surface and in the entire film.
Patent Document 2 discloses a virus removal membrane in which a polysaccharide derivative is coated on a blend membrane of a polysulfone polymer, a vinyl pyrrolidone, and a vinyl acetate copolymer.
特許文献１では、膜厚方向に親水性高分子を均一に分散させることにより、タンパク質の膜への吸着のリスクが膜全体で同レベルであるとしている。しかし、タンパク質溶液濾過中のタンパク質の膜への吸着による目詰まりを抑制するためには、膜中の孔径の最も小さい領域である緻密層でのタンパク質の吸着を抑制する必要があるが、この課題は解決されていない。
特許文献２では、特許文献１と同様の方法で製膜した中空糸膜に多糖類誘導体を製膜後にコーティングすることにより、タンパク質溶液濾過中のタンパク質の膜への吸着による目詰まりを抑制している。このことから、特許文献１の方法で製膜された中空糸膜における親水性高分子の膜中の分散状態では、タンパク質の膜への吸着を十分に抑制できないことが推察される。また、製膜後に多糖類誘導体をコーティングすると、孔表面上の多糖類誘導体の分散状態の不均一性から、ビニルピロリドンと酢酸ビニルの共重合体の分散状態に不均一性が生じるため、孔表面上でのタンパク質の吸着のリスクが同レベルとならず、局所的なタンパク質の吸着が周囲に伝播し、目詰まりが起こるリスクが生じる。そして、タンパク質溶液を濾過することを目的とする膜においては、緻密層でのタンパク質の吸着を抑制する必要があるが、この課題はやはり解決されていない。In Patent Document 1, the hydrophilic polymer is uniformly dispersed in the film thickness direction so that the risk of protein adsorption to the film is at the same level throughout the film. However, in order to suppress clogging due to the adsorption of proteins to the membrane during protein solution filtration, it is necessary to suppress the adsorption of proteins in the dense layer, which is the region with the smallest pore size in the membrane. Is not solved.
In Patent Document 2, clogging due to protein adsorption during protein solution filtration is suppressed by coating a polysaccharide derivative on the hollow fiber membrane formed by the same method as Patent Document 1 after film formation. Yes. From this, it is surmised that the adsorption of the protein to the membrane cannot be sufficiently suppressed in the dispersed state in the membrane of the hydrophilic polymer in the hollow fiber membrane formed by the method of Patent Document 1. In addition, if the polysaccharide derivative is coated after film formation, the dispersion state of the vinyl pyrrolidone and vinyl acetate copolymer will be uneven due to the heterogeneity of the dispersion state of the polysaccharide derivative on the pore surface. The risk of protein adsorption above does not become the same level, and local protein adsorption propagates to the surroundings, causing clogging. And in the film | membrane aiming at filtering a protein solution, although it is necessary to suppress adsorption | suction of the protein in a precise | minute layer, this subject is not solved yet.
本発明が解決しようとする課題は、タンパク質溶液濾過中の緻密層の細孔表面へのタンパク質の吸着を抑制し、タンパク質透過性に優れた多孔質中空糸濾過膜を提供することである。 The problem to be solved by the present invention is to provide a porous hollow fiber filtration membrane excellent in protein permeability by suppressing protein adsorption to the pore surface of a dense layer during protein solution filtration.
本発明者らは、上記課題を解決するために鋭意検討した結果、外表面及び膜中での親水性高分子の含有率を制御することにより、上記課題を解決することを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by controlling the content of the hydrophilic polymer in the outer surface and the membrane, and the present invention completed.
すなわち、本発明は、以下の通りである。
（１）
ポリスルホン系高分子と親水性高分子を含み、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造を有し、膜中の親水性高分子の含有率が６．０〜１２．０質量％であり、外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比が１．２０〜１．６０である多孔質中空糸濾過膜。
（２）
純水の透過速度が６０〜２００Ｌ／（ｈｒ・ｍ2・ｂａｒ）である、（１）に記載の多孔質中空糸濾過膜。
（３）
緻密層の厚みが２〜１０μｍである、（１）または（２）に記載の多孔質中空糸濾過膜。
（４）
前記ポリスルホン系高分子が、ポリエーテルスルホンである、（１）〜（３）のいずれかに記載の多孔質中空糸濾過膜。
（５）
前記親水性高分子が、ビニルピロリドンを含有する共重合体である、（１）〜（４）のいずれかに記載の多孔質中空糸濾過膜。
（６）
タンパク質溶液に含まれるウイルスを除去し、タンパク質を回収するのに用いられる、（１）〜（５）のいずれかに記載の多孔質中空糸濾過膜。That is, the present invention is as follows.
(1)
It contains a polysulfone polymer and a hydrophilic polymer, has an inclined asymmetric structure in which the average pore diameter increases from the outer surface toward the inner surface, and the content of the hydrophilic polymer in the membrane is 6.0. A porous hollow fiber filtration membrane having a ratio of the content of the hydrophilic polymer on the outer surface to the content of the hydrophilic polymer in the membrane of 1.20 to 1.60.
(2)
The porous hollow fiber filtration membrane according to (1), wherein the permeation rate of pure water is 60 to 200 L / (hr · m 2 · bar).
(3)
The porous hollow fiber filtration membrane according to (1) or (2), wherein the dense layer has a thickness of 2 to 10 μm.
(4)
The porous hollow fiber filtration membrane according to any one of (1) to (3), wherein the polysulfone-based polymer is polyethersulfone.
(5)
The porous hollow fiber filtration membrane according to any one of (1) to (4), wherein the hydrophilic polymer is a copolymer containing vinylpyrrolidone.
(6)
The porous hollow fiber filtration membrane according to any one of (1) to (5), which is used for removing a virus contained in a protein solution and recovering a protein.
本発明によれば、濾過中の細孔表面へのタンパク質の吸着を抑制し、タンパク質透過性に優れた多孔質中空糸濾過膜を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, adsorption | suction of the protein to the pore surface during filtration can be suppressed, and the porous hollow fiber filtration membrane excellent in protein permeability can be provided.
以下、本発明を実施するための形態（以下、「本実施形態」という。）について詳細に説明する。本発明は、以下の実施形態に限定されるものではなく、その要旨の範囲内で種々変形して実施できる。 Hereinafter, a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail. The present invention is not limited to the following embodiments, and various modifications can be made within the scope of the gist.
本実施形態の多孔質中空糸濾過膜は、ポリスルホン系高分子と親水性高分子を含み、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造を有し、膜中の親水性高分子の含有率が６．０〜１２．０質量％であり、外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比が１．２０〜１．６０である。 The porous hollow fiber filtration membrane of the present embodiment includes a polysulfone-based polymer and a hydrophilic polymer, and has an inclined asymmetric structure in which the average pore diameter of pores increases from the outer surface toward the inner surface. The content of the hydrophilic polymer is 6.0 to 12.0% by mass, and the ratio of the content of the hydrophilic polymer on the outer surface to the content of the hydrophilic polymer in the film is 1.20 to 1. .60.
本実施形態の多孔質中空糸濾過膜は、ポリスルホン系高分子と親水性高分子を含む。
ポリスルホン系高分子とは、下記式１で示される繰り返し単位を有するポリスルホンであるか、下記式２で示される繰り返し単位を有するポリエーテルスルホンである。
ポリスルホン系高分子のうち、溶液中での会合体の形成防止等、溶解性の観点で、ポリエーテルスルホンが好ましい。The porous hollow fiber filtration membrane of this embodiment contains a polysulfone polymer and a hydrophilic polymer.
The polysulfone polymer is a polysulfone having a repeating unit represented by the following formula 1 or a polyethersulfone having a repeating unit represented by the following formula 2.
Of the polysulfone-based polymers, polyethersulfone is preferable from the viewpoint of solubility such as prevention of formation of aggregates in a solution.
式１：
式２：
ポリスルホン系高分子としては、式１や式２で示される構造において、官能基やアルキル基等の置換基を含んでもよく、炭化水素骨格の水素原子はハロゲン等の他の原子や置換基で置換されてもよい。
ポリスルホン系高分子は、単独で使用しても、２種以上を混合して使用してもよい。The polysulfone polymer may contain a substituent such as a functional group or an alkyl group in the structure represented by Formula 1 or Formula 2, and the hydrogen atom of the hydrocarbon skeleton is substituted with another atom or substituent such as halogen. May be.
Polysulfone polymers may be used alone or in admixture of two or more.
親水性高分子はポリスルホン系高分子と相溶するものであれば、特に限定されないが、ポリスルホン系高分子との相溶性が高く、製膜原液中に親水性高分子を多く混合できるという点で、ビニルピロリドンを含有する共重合体が好ましい。
ビニルピロリドンを含有する共重合体としては、ポリスルホン系高分子との相溶性の観点で、ビニルピロリドンと酢酸ビニルの共重合体が好ましい。ビニルピロリドンと酢酸ビニルの共重合比は、タンパク質の膜表面への吸着やポリスルホン系高分子との膜中での相互作用の観点から、６：４から９：１が好ましい。
ビニルピロリドンと酢酸ビニルの共重合体としては、具体的には、ＢＡＳＦ社より市販されているＬＵＶＩＳＫＯＬ（商品名）ＶＡ６４及びＶＡ７３等が挙げられる。
親水性高分子は、単独で使用しても、２種以上を混合して使用してもよい。The hydrophilic polymer is not particularly limited as long as it is compatible with the polysulfone polymer, but it is highly compatible with the polysulfone polymer and can be mixed with a large amount of the hydrophilic polymer in the film forming stock solution. A copolymer containing vinylpyrrolidone is preferred.
The copolymer containing vinylpyrrolidone is preferably a copolymer of vinylpyrrolidone and vinyl acetate from the viewpoint of compatibility with the polysulfone polymer. The copolymerization ratio of vinylpyrrolidone and vinyl acetate is preferably 6: 4 to 9: 1 from the viewpoint of protein adsorption on the membrane surface and interaction with the polysulfone polymer in the membrane.
Specific examples of the copolymer of vinyl pyrrolidone and vinyl acetate include LUVISKOL (trade name) VA64 and VA73 commercially available from BASF.
The hydrophilic polymer may be used alone or in combination of two or more.
本実施形態の多孔質中空糸濾過膜は、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造を有する。
本実施形態において、内表面とは、多孔質中空糸濾過膜における中空糸の中空部側の表面を意味し、外表面とは、中空部表面とは膜厚方向に反対側の膜表面を意味する。The porous hollow fiber filtration membrane of this embodiment has an inclined asymmetric structure in which the average pore diameter of pores increases from the outer surface toward the inner surface.
In this embodiment, the inner surface means the surface of the hollow portion of the hollow fiber filtration membrane on the hollow portion side, and the outer surface means the surface of the membrane opposite to the hollow portion surface in the film thickness direction. To do.
多孔質中空糸濾過膜が、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造であることは、中空糸断面を走査型電子顕微鏡（ＳＥＭ）により撮影することで決定される。例えば、撮影倍率を５０，０００倍に設定し、中空糸断面の任意の部位において膜厚方向に対して水平に視野を設定する。設定した一視野での撮影後、膜厚方向に対して水平に撮影視野を移動し、次の視野を撮影する。この撮影操作を繰り返し、隙間なく膜断面の写真を撮影し、得られた写真を結合することで一枚の膜断面写真を得る。この断面写真において、（膜の円周方向に２μｍ）×（外表面から内表面側に向かって１μｍ）の範囲における平均孔径を算出し、外表面から内表面側に向かって１μｍ毎に膜断面の傾斜構造を数値化する。
かかる数値化により、多孔質中空糸濾過膜が、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型多孔質構造を有することを確認することができる。
本実施形態において、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造を有するとは、外表面から内表面に向かって、平均孔径が大きくなる傾向があることが確認できる構造であればよく、外表面から内表面側に向かって１μｍの範囲の平均孔径が最小であり、内表面から外表面側に向かって１μｍの範囲の平均孔径が最大であることを意味しない。The fact that the porous hollow fiber filtration membrane has an inclined asymmetric structure in which the average pore diameter of the pores increases from the outer surface toward the inner surface is determined by photographing the cross section of the hollow fiber with a scanning electron microscope (SEM). Is done. For example, the photographing magnification is set to 50,000 times, and the field of view is set horizontally with respect to the film thickness direction at an arbitrary portion of the hollow fiber cross section. After photographing with one set visual field, the photographing visual field is moved horizontally with respect to the film thickness direction, and the next visual field is photographed. This photographing operation is repeated, a photograph of the film cross section is taken without gaps, and a single film cross-sectional photograph is obtained by combining the obtained photographs. In this cross-sectional photograph, the average pore diameter in the range of (2 μm in the circumferential direction of the membrane) × (1 μm from the outer surface to the inner surface side) is calculated, and the membrane cross section is taken every 1 μm from the outer surface to the inner surface side. Quantify the slant structure.
By such numerical conversion, it can be confirmed that the porous hollow fiber filtration membrane has an inclined porous structure in which the average pore diameter of the pores increases from the outer surface toward the inner surface.
In this embodiment, having an inclined asymmetric structure in which the average pore diameter of pores increases from the outer surface to the inner surface confirms that the average pore diameter tends to increase from the outer surface to the inner surface. Any structure can be used, and the average pore diameter in the range of 1 μm from the outer surface to the inner surface side is the smallest, and the average pore diameter in the range of 1 μm from the inner surface to the outer surface side is not the largest. .
平均孔径の算出方法は、画像解析を用いた方法で算出する。具体的には、ＭｅｄｉａＣｙｂｅｒｂｅｔｉｃｓ社製Ｉｍａｇｅ−ｐｒｏ ｐｌｕｓを用いて空孔部と実部の二値化処理を行う。明度を基準に空孔部と実部を識別し、識別できなかった部分やノイズをフリーハンドツールで補正する。空孔部の輪郭となるエッジ部分や、空孔部の奥に観察される多孔構造は空孔部として識別する。二値化処理の後、空孔／１個の面積値を真円と仮定し、空孔の直径を算出する。全ての空孔毎に実施し、１μｍ×２μｍの範囲毎に平均孔径を算出していく。なお、視野の端部で途切れた空孔部についてもカウントすることとする。
本実施形態においては、平均孔径が５０ｎｍ以下であると算出された１μｍ×２μｍの範囲は緻密層と定義する。The average pore diameter is calculated by a method using image analysis. Specifically, binarization processing of the hole portion and the real portion is performed using Image-pro plus manufactured by Media Cyberbertics. The hole part and the real part are identified based on the brightness, and the part or noise that cannot be identified is corrected with a freehand tool. The edge part which becomes the outline of a void | hole part and the porous structure observed in the back of a void | hole part are identified as a void | hole part. After the binarization process, the hole diameter is calculated assuming that the hole / area value is a perfect circle. This is carried out for every hole, and the average hole diameter is calculated for each range of 1 μm × 2 μm. It should be noted that holes are also counted at the edge of the field of view.
In the present embodiment, the range of 1 μm × 2 μm calculated to have an average pore diameter of 50 nm or less is defined as a dense layer.
緻密層における細孔が閉塞されるとＦｌｕｘが低下する。すなわち、膜のＦｌｕｘは、緻密層の厚さ、及び緻密層における孔径に支配される。
濾過上流側から濾過下流側に向けて、細孔の平均孔径が小さくなる膜は、濾過上流において大きな粒子を捕捉でき、大きな粒子の緻密層の閉塞によるＦｌｕｘの低下を抑制することができる。
本実施形態においては、多孔質中空糸濾過膜が、細孔の平均孔径が外表面から内表面に向かって大きくなる傾斜型非対称構造を有するため、外表面側にある緻密層における細孔の閉塞によるＦｌｕｘの低下を抑制することができる。When pores in the dense layer are blocked, the flux decreases. That is, the flux of the film is governed by the thickness of the dense layer and the pore diameter in the dense layer.
A membrane in which the average pore diameter of the pores decreases from the upstream side of the filtration toward the downstream side of the filtration can capture large particles upstream of the filtration, and can suppress the decrease in flux due to the blockage of the dense layer of large particles.
In this embodiment, the porous hollow fiber filtration membrane has an inclined asymmetric structure in which the average pore diameter of the pores increases from the outer surface toward the inner surface, so that the pores are blocked in the dense layer on the outer surface side. It is possible to suppress the decrease in flux due to the above.
緻密層における細孔の閉塞には２種類ある。
一つは、溶質のサイズよりも小さい細孔が、溶質により閉塞されるというサイズを因子（サイズ因）とするものであり、もう一つは、溶質が細孔表面に吸着することにより、細孔が閉塞されるという吸着を因子（吸着因）とするものである。
サイズ因による細孔の閉塞は濾過中断続的に起こり、吸着因による細孔の閉塞は、主に、濾過初期に観察される。
タンパク質透過性を向上させるためには、サイズ因に加え、緻密層における細孔表面へのタンパク質の吸着を抑制し、濾過初期の著しいＦｌｕｘ低下を抑制することが重要である。There are two types of pore blockage in the dense layer.
One is the factor (size factor) that the pores smaller than the size of the solute are clogged by the solute, and the other is that the solute adsorbs on the pore surface and becomes finer. Adsorption that a hole is blocked is a factor (adsorption factor).
The clogging of the pores due to the size factor occurs intermittently during the filtration, and the clogging of the pores due to the adsorption factor is mainly observed in the early stage of the filtration.
In order to improve protein permeability, in addition to the size factor, it is important to suppress protein adsorption to the pore surface in the dense layer, and to suppress a remarkable decrease in flux at the beginning of filtration.
本実施形態の多孔質中空糸濾過膜は、膜中の親水性高分子の含有率が６．０〜１２．０質量％であり、外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比が１．２０〜１．６０である。
本実施形態においては、外表面及び膜中での親水性高分子の含有量を制御することにより、緻密層における細孔表面へのタンパク質の吸着を抑制し、吸着によるＦｌｕｘ低下を抑制することができる。
外表面及び膜中での親水性高分子の含有量として、膜中の親水性高分子の含有率を６．０〜１２．０質量％とすることにより、孔表面上の親水性高分子の厚みによる細孔の縮小を抑制することができる。また、外表面及び膜中での親水性高分子の含有量として、膜中の親水性高分子の含有率を６．０〜１２．０質量％とし、外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比を１．２０〜１．６０とすることにより、Ｆｌｕｘ低下を抑制することができる。The porous hollow fiber filtration membrane of this embodiment has a hydrophilic polymer content in the membrane of 6.0 to 12.0 mass%, and the hydrophilic polymer content in the outer surface and the hydrophilicity in the membrane. The ratio of the content of the functional polymer is 1.20 to 1.60.
In the present embodiment, by controlling the content of the hydrophilic polymer in the outer surface and the membrane, it is possible to suppress protein adsorption to the pore surface in the dense layer and to suppress decrease in flux due to adsorption. it can.
By setting the content of the hydrophilic polymer in the membrane to 6.0 to 12.0 mass% as the content of the hydrophilic polymer in the outer surface and the membrane, Reduction of pores due to thickness can be suppressed. Moreover, as content of the hydrophilic polymer in an outer surface and a film | membrane, the content rate of the hydrophilic polymer in a film | membrane shall be 6.0-12.0 mass%, and the content rate of the hydrophilic polymer in an outer surface And the ratio of the content of the hydrophilic polymer in the film is 1.20 to 1.60, the decrease in flux can be suppressed.
本実施形態においては、親水性高分子の外表面及び膜中の含有量の測定は以下のようにして行う。
多孔質中空糸濾過膜を厚さ１０μｍで膜厚方向に切断する。切断した多孔質中空糸濾過膜断片を臭化カリウム板ではさみ、５×５μｍを１セグメントとし、顕微ＦＴ−ＩＲにより透過法で膜厚方向に連続的に測定する。測定したスペクトルよりポリスルホン系高分子由来のピーク（１５８０ｃｍ-1付近）と親水性高分子由来のピーク（例えば、カルボニル結合を有する親水性高分子ならば、１７３０ｃｍ-1付近、例えば、エーテル結合を有する親水性高分子ならば、１１００ｃｍ-1付近）を検出し、親水性高分子由来のピークの吸光度面積／ポリスルホン系高分子由来のピークの吸光度面積比より、各分割したセグメントにおける親水性高分子の含有率として算出する。
各セグメントの親水性高分子の含有率の平均値を親水性高分子の膜中の含有率とする。
膜厚方向で最外表面側のセグメントの親水性高分子の含有率／親水性高分子の膜中の含有率を外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比として算出する。In the present embodiment, the content of the hydrophilic polymer on the outer surface and in the film is measured as follows.
The porous hollow fiber filtration membrane is cut in the thickness direction with a thickness of 10 μm. The cut piece of the porous hollow fiber filtration membrane is sandwiched with a potassium bromide plate, and 5 × 5 μm is defined as one segment, and continuously measured in the film thickness direction by microscopic FT-IR by the transmission method. From the measured spectrum, a peak derived from a polysulfone polymer (near 1580 cm −1 ) and a peak derived from a hydrophilic polymer (for example, a hydrophilic polymer having a carbonyl bond has a vicinity of 1730 cm −1 , for example, an ether bond. In the case of a hydrophilic polymer, the vicinity of 1100 cm -1 is detected, and the ratio of the absorbance of the hydrophilic polymer to the peak / the absorbance of the polysulfone-based polymer is calculated based on the ratio of the absorbance of the hydrophilic polymer in each segment. Calculated as content.
Let the average value of the content rate of the hydrophilic polymer of each segment be the content rate in the film of the hydrophilic polymer.
The content of hydrophilic polymer in the segment on the outermost surface side in the film thickness direction / the content of hydrophilic polymer in the film, the content of hydrophilic polymer in the outer surface and the content of hydrophilic polymer in the film Calculated as a ratio of rates.
本実施形態において、緻密層において、濾過初期のタンパク質の吸着によるＦｌｕｘ低下を抑制し、優れたタンパク質透過性を示すことは免疫グロブリンの濾過試験により確認することができる。
免疫グロブリンの濾過試験は実施例に記載の方法により行うことができる。
免疫グロブリンの濾過試験において、Ｆｌｕｘ低下を抑制しているということは、１．５質量％の免疫グロブリンを２．０ｂａｒで定圧濾過したときの、濾過開始後５分経過時のＦｌｕｘ（Ｆ5）と純水を１．０ｂａｒで定圧濾過した時の透水量を２倍した値（Ｆｗ）の比（Ｆ5／Ｆｗ）が０．５０以上であることである。In the present embodiment, it can be confirmed by an immunoglobulin filtration test that the dense layer suppresses the decrease in flux due to protein adsorption in the initial stage of filtration and exhibits excellent protein permeability.
The immunoglobulin filtration test can be performed by the method described in the Examples.
In the immunoglobulin filtration test, the decrease in flux is suppressed, which means that flux (F 5 ) after 5 minutes from the start of filtration when 1.5% by mass of immunoglobulin is filtered at a constant pressure of 2.0 bar. And the ratio (F 5 / Fw) of the value (Fw) obtained by doubling the water permeation amount when pure water is filtered at a constant pressure of 1.0 bar is 0.50 or more.
有用成分であるタンパク質の透過性を向上させるためには、緻密層におけるタンパク質の吸着を抑制することに加え、高い濾過圧で操作できることが好ましい。濾過圧を高く設定することにより、Ｆｌｕｘを高くすることができるからである。
高い濾過圧での操作は、基材に耐圧性を有するポリスルホン系高分子を用いることにより実現される。In order to improve the permeability of the protein which is a useful component, it is preferable that the protein can be operated at a high filtration pressure in addition to suppressing the adsorption of the protein in the dense layer. This is because the flux can be increased by setting the filtration pressure high.
The operation at a high filtration pressure is realized by using a polysulfone polymer having pressure resistance for the substrate.
タンパク質の透過性をさらに向上させるためには、ウイルス除去性能を発揮し得る範囲内で、純水の透過速度を高くすることが好ましい。純水の透過速度はタンパク質溶液の濾過速度Ｆｌｕｘの目安となる。
タンパク質溶液は純水に比べ溶液の粘度が高くなるため、純水の透過速度よりも低くなるが、純水の透過速度が高いほど、タンパク質溶液の濾過速度は高くなる。本実施形態の多孔質中空糸濾過膜の純水の透過速度は６０〜２００Ｌ／（ｈｒ・ｍ2・ｂａｒ）が好ましく、１００〜１８０Ｌ／（ｈｒ・ｍ2・ｂａｒ）がより好ましい。
純水の透過速度が６０Ｌ／（ｈｒ・ｍ2・ｂａｒ）以上であることにより、濾過時間が長過ぎず、高効率にタンパク質を回収可能である。また、純水の透過速度が２００Ｌ／（ｈｒ・ｍ2・ｂａｒ）以下であることにより、ウイルス除去性能を発揮することができる。
純水の透過速度は実施例に記載の方法により測定することができる。In order to further improve the permeability of the protein, it is preferable to increase the permeation rate of pure water within a range where the virus removal performance can be exhibited. The permeation rate of pure water is a measure of the filtration rate Flux of the protein solution.
The protein solution has a higher viscosity than that of pure water, and thus is lower than the permeation rate of pure water. However, the higher the permeation rate of pure water, the higher the filtration rate of the protein solution. Permeation rate of the pure water of the porous hollow fiber filtration membrane of the present embodiment 60~200L / (hr · m 2 · bar) are preferred, 100~180L / (hr · m 2 · bar) is more preferable.
When the permeation rate of pure water is 60 L / (hr · m 2 · bar) or more, the filtration time is not too long and the protein can be recovered with high efficiency. Moreover, when the permeation rate of pure water is 200 L / (hr · m 2 · bar) or less, virus removal performance can be exhibited.
The permeation rate of pure water can be measured by the method described in the examples.
ウイルス除去膜におけるウイルス除去機構は下記のように考えられている。
ウイルスを含んだタンパク質溶液は透過方向に対して垂直なウイルス捕捉面が何層も重なったウイルス除去層を透過する。
ウイルス捕捉面中の細孔の大きさには必ず分布が存在し、ウイルスのサイズよりも小さな細孔の部分でウイルスが捕捉される。一つのウイルス捕捉面でのウイルス捕捉率は低いが、ウイルス捕捉面が何層も重なることにより、高いウイルス除去性能が実現される。例えば、一つのウイルス捕捉面でのウイルス捕捉率が２０％であっても、ウイルス捕捉面が５０層重なることにより、全体としてのウイルス捕捉率は９９．９９９％となる。
ウイルス除去膜では、ウイルスは多層で捕捉することによりウイルス捕捉能力を高くすることができるため、緻密層を厚くすることが好ましい。タンパク質のＦｌｕｘ低下抑制の観点から、緻密層の厚さを一定の範囲内にすることが好ましい。
ウイルス除去の安全性とタンパク質回収効率の生産性を両立させる観点から、緻密層の厚さは２〜１０μｍであることが好ましく、２〜８μｍであることがより好ましい。The mechanism of virus removal in the virus removal membrane is considered as follows.
The protein solution containing the virus passes through the virus removal layer in which the virus capturing surfaces perpendicular to the permeation direction overlap each other.
There is always a distribution in the size of the pores in the virus trapping surface, and the virus is trapped in the pores smaller than the size of the virus. Although the virus capture rate on one virus capture surface is low, a high virus removal performance is realized by overlapping the layers of the virus capture surface. For example, even if the virus capture rate on one virus capture surface is 20%, the virus capture rate as a whole is 99.999% by overlapping 50 layers of virus capture surfaces.
In the virus removal membrane, it is preferable to increase the thickness of the dense layer because the virus can be captured in multiple layers to increase the ability of capturing the virus. From the viewpoint of suppressing protein flux reduction, it is preferable to set the thickness of the dense layer within a certain range.
The thickness of the dense layer is preferably 2 to 10 μm, more preferably 2 to 8 μm, from the viewpoint of achieving both virus removal safety and protein recovery efficiency productivity.
本実施形態の多孔質中空糸濾過膜のパルボウイルスクリアランスは、ＬＲＶとして４．０以上が好ましく、５．０以上であることがより好ましい。
パルボウイルスとして、実液に近いもの、操作性の簡便性からブタパルボウイルス（ＰＰＶ）であることが好ましい。
ＰＰＶのＬＲＶは実施例に記載の方法により測定することができる。The parvovirus clearance of the porous hollow fiber filtration membrane of the present embodiment is preferably 4.0 or higher, more preferably 5.0 or higher, as LRV.
The parvovirus is preferably a porcine parvovirus (PPV) because it is close to a real liquid and easy to operate.
The LRV of PPV can be measured by the method described in Examples.
本実施形態において、多孔質中空糸濾過膜は、特に限定されるものではないが、以下のようにして製造することができる。
例えば、ポリスルホン系高分子、親水性高分子、及び溶媒を混合溶解し、脱泡したものを製膜原液とし、内液（芯液）とともに、二重管ノズル（紡口）の環状部、中心部からそれぞれ同時に吐出し、空走部を経て凝固液中に導いて中空糸を形成する。得られた中空糸を、水洗後巻取り、中空部内の液抜き、熱処理、乾燥させる。In the present embodiment, the porous hollow fiber filtration membrane is not particularly limited, but can be produced as follows.
For example, a polysulfone polymer, a hydrophilic polymer, and a solvent are mixed and dissolved and defoamed to form a film-forming stock solution, along with the inner liquid (core liquid), the annular part of the double-tube nozzle (spinner), the center It discharges simultaneously from each part and guides into the coagulation liquid through the idle running part to form a hollow fiber. The obtained hollow fiber is wound after washing with water, drained from the hollow portion, heat-treated, and dried.
製膜原液に使用される溶媒は、ポリスルホン系高分子と親水性高分子の良溶媒であり、かつ、ポリスルホン系高分子と親水性高分子が相溶する溶媒であれば、広く使用することができるが、例えば、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ−ジメチルアセトアミド（ＤＭＡｃ）、ジメチルスルホキシド、及びε―カプロラクタム等が挙げられ、ＮＭＰ、ＤＭＦ、及びＤＭＡｃ等のアミド系溶媒が好ましく、ＮＭＰがより好ましい。 The solvent used for the film-forming stock solution is a good solvent for polysulfone polymers and hydrophilic polymers, and can be widely used as long as the solvent is compatible with polysulfone polymers and hydrophilic polymers. Examples thereof include N-methyl-2-pyrrolidone (NMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethyl sulfoxide, and ε-caprolactam, and the like. Amide solvents such as DMF and DMAc are preferred, and NMP is more preferred.
製膜原液には非溶媒を添加するのが好ましい。製膜原液に使用される非溶媒としては、例えば、グリセリン、水、及びジオール化合等が挙げられ、ジオール化合物が好ましい。
ジオール化合物とは、分子の両末端に水酸基を有する化合物であり、ジオール化合物としては、下記式３で表され、繰り返し単位ｎが１以上のエチレングリコール構造を有する化合物が好ましい。
ジオール化合物としては、例えば、ジエチレングリコール（ＤＥＧ）、トリエチレングリコール（ＴｒｉＥＧ）、テトラエチレングリコール（ＴｅｔｒａＥＧ）、及びポリエチレングリコール等が挙げられ、ＤＥＧ、ＴｒｉＥＧ、及びＴｅｔｒａＥＧが好ましく、ＴｒｉＥＧがより好ましい。It is preferable to add a non-solvent to the film-forming stock solution. Examples of the non-solvent used in the film-forming stock solution include glycerin, water, and a diol compound, and a diol compound is preferable.
The diol compound is a compound having hydroxyl groups at both ends of the molecule, and the diol compound is preferably a compound represented by the following formula 3 and having an ethylene glycol structure in which the repeating unit n is 1 or more.
Examples of the diol compound include diethylene glycol (DEG), triethylene glycol (TriEG), tetraethylene glycol (TetraEG), polyethylene glycol, and the like. DEG, TriEG, and TetraEG are preferable, and TriEG is more preferable.
式３：
製膜原液中の溶媒／非溶媒の質量比は、同量程度であればよく、３５／６５〜６５／３５が好ましい。非溶媒の量が質量比として６５／３５以下であると、凝固が適度な速さで進行するため、過度に大きな孔径が生じにくく、タンパク質溶液の処理用途の濾過膜として好ましい膜構造を有する多孔質中空糸濾過膜を得ることができる。非溶媒の量が質量比として３５／６５以上であることで、凝固の進行が速すぎないので、過度に小さな孔径が生じにくく、また、構造欠陥となるマクロボイドも生じにくいため、好ましい。 The mass ratio of the solvent / non-solvent in the film-forming stock solution may be about the same amount, and is preferably 35/65 to 65/35. When the amount of the non-solvent is 65/35 or less as a mass ratio, coagulation proceeds at an appropriate speed, so that an excessively large pore diameter is hardly generated, and the porous structure has a preferable membrane structure as a filtration membrane for protein solution processing. A hollow fiber filtration membrane can be obtained. It is preferable that the amount of the non-solvent is 35/65 or more as a mass ratio because the progress of solidification is not too fast, so that excessively small pore diameters are hardly generated and macrovoids that are structural defects are not easily generated.
製膜原液中のポリスルホン系高分子の濃度は１５〜３５質量％が好ましく、２０〜３０質量％がより好ましい。
製膜原液中のポリスルホン系高分子の濃度を１５質量％以上とすることにより、適当な膜強度とすることができると共に、空孔率を上げることにより高い透過性能を得ることができる。製膜原液中のポリスルホン系高分子の濃度を３５質量％以下にすることにより、空孔率が低くなり過ぎず、透過性能を維持できるだけでなく、膜のウイルス捕捉容量が高く保つことができる。The concentration of the polysulfone polymer in the membrane forming stock solution is preferably 15 to 35% by mass, and more preferably 20 to 30% by mass.
By setting the concentration of the polysulfone polymer in the membrane forming stock solution to 15% by mass or more, it is possible to obtain an appropriate membrane strength, and it is possible to obtain high permeation performance by increasing the porosity. By setting the concentration of the polysulfone polymer in the membrane-forming stock solution to 35% by mass or less, the porosity is not lowered too much, not only the permeation performance can be maintained, but also the membrane virus capture capacity can be kept high.
製膜原液中の親水性高分子の濃度は５〜１２質量％が好ましい。
製膜原液中の親水性高分子の濃度が５質量％以上とすることにより、得られる膜が十分に親水性化される。タンパク質溶液の濾過に使用する場合でも、タンパク質が膜に吸着しにくく、Ｆｌｕｘ低下が起こり難い観点で、濃度が５質量％以上であることが好ましい。製膜原液中の親水性高分子の濃度を１２質量％以下とすることにより、得られる膜において孔表面上の親水性高分子の厚みが厚過ぎず、過度に孔径が小さくならないので好ましい。また、乾燥後に中空糸同士が固着する糸付きを防止する観点で、濃度を１２質量％以下であることが好ましい。The concentration of the hydrophilic polymer in the film forming stock solution is preferably 5 to 12% by mass.
By setting the concentration of the hydrophilic polymer in the film-forming stock solution to 5% by mass or more, the resulting film is sufficiently hydrophilic. Even when used for filtration of a protein solution, the concentration is preferably 5% by mass or more from the viewpoint that the protein is less likely to be adsorbed on the membrane and the flux is not easily lowered. By setting the concentration of the hydrophilic polymer in the film-forming stock solution to 12% by mass or less, the thickness of the hydrophilic polymer on the pore surface in the resulting membrane is not too thick, and the pore diameter is not excessively reduced. Moreover, it is preferable that a density | concentration is 12 mass% or less from a viewpoint of preventing the sticking with which a hollow fiber adheres after drying.
製膜原液は、ポリスルホン系高分子、親水性高分子、溶媒、及び非溶媒を一定温度で、撹拌しながら溶解することで得られる。この時の温度は、常温より高い、３０〜６０℃が好ましい。３級以下の窒素を含有する化合物（ＮＭＰ及びビニルピロリドン等）は空気中で酸化され、加温するとさらに酸化が進行しやすくなるため、製膜原液の調製は不活性気体雰囲気下で行うことが好ましい。不活性気体としては、窒素及びアルゴン等が挙げられ、生産コストの観点から窒素が好ましい。 The film-forming stock solution can be obtained by dissolving a polysulfone polymer, a hydrophilic polymer, a solvent, and a non-solvent at a constant temperature with stirring. The temperature at this time is preferably 30 to 60 ° C., which is higher than normal temperature. A compound containing nitrogen of grade 3 or less (NMP, vinylpyrrolidone, etc.) is oxidized in the air, and when heated, the oxidation proceeds more easily. Therefore, the film forming stock solution should be prepared in an inert gas atmosphere. preferable. Examples of the inert gas include nitrogen and argon, and nitrogen is preferable from the viewpoint of production cost.
製膜原液中に気泡が存在すると、大きな気泡は紡糸中の糸切れの原因となり、小さな気泡は製膜後にマクロボイドを形成し、膜の構造欠陥の原因となるため、脱泡することが好ましい。
脱泡工程は以下のように行うことができる。
完全に溶解された製膜原液が入ったタンク内を５０℃に加温し、２ｋＰａまで減圧し、１時間以上静置する。この操作を７回以上繰り返すことが好ましい。脱泡するときの圧力は溶媒の沸点より高くすることが好ましい。脱泡効率をあげるため、脱泡中に製膜原液を撹拌してもよい。When bubbles are present in the film-forming stock solution, large bubbles cause thread breakage during spinning, and small bubbles form macrovoids after film formation and cause structural defects in the film. .
The defoaming step can be performed as follows.
The inside of the tank containing the completely dissolved film forming stock solution is heated to 50 ° C., depressurized to 2 kPa, and left to stand for 1 hour or longer. This operation is preferably repeated 7 times or more. The pressure for defoaming is preferably higher than the boiling point of the solvent. In order to increase the defoaming efficiency, the film-forming stock solution may be stirred during the defoaming.
製膜原液は、紡口から吐出される前までに、異物を除去することが好ましい。大きな異物は紡糸中の糸切れの原因となり、小さな異物は膜の構造欠陥の原因となる。異物の少ない原料を用いることにより、異物の混入リスクは低減できる。
製膜原液タンクのパッキン等からの異物の混入を除去するために、製膜原液が紡口から吐出される前に、フィルターを設置することが好ましく、孔径違いのフィルターを多段で設置することがより好ましい。具体的には、製膜原液タンクに近い方から、順に孔径１０μｍのメッシュフィルター、孔径３μｍのメッシュフィルターを設置するのが好ましい。It is preferable to remove foreign substances before the film-forming stock solution is discharged from the spinning nozzle. Large foreign matter causes thread breakage during spinning, and small foreign matter causes structural defects in the film. By using a raw material with less foreign matter, the risk of foreign matter contamination can be reduced.
In order to remove foreign matter from the packing of the membrane forming stock solution tank, it is preferable to install a filter before the membrane forming stock solution is discharged from the spinning nozzle, and it is possible to install filters with different pore sizes in multiple stages. More preferred. Specifically, it is preferable to install a mesh filter with a pore diameter of 10 μm and a mesh filter with a pore diameter of 3 μm in order from the side closer to the film-forming stock solution tank.
製膜時に使用される内液として、製膜原液及び凝固液に使用される成分と同じ成分を使用することが好ましい。製膜原液の溶媒／非溶媒として、例えばＮＭＰ／ＴｒｉＥＧ、凝固液の溶媒／非溶媒としてＮＭＰ／ＴｒｉＥＧ及び水を使用したならば、内液は、ＮＭＰ／ＴｒｉＥＧ及び水から構成されることが好ましい。
内液中の溶媒量が多くなると、凝固の進行を遅らせ、膜構造形成をゆっくりと進行させる効果があり、非溶媒量が多くなると、増粘効果により、溶液の拡散を遅らし、凝固の進行を遅らせ、膜構造形成をゆっくりと進行させる効果があり、水が多くなると、凝固の進行を早める効果がある。
凝固の進行を適切に進行させ、膜構造を制御し、本実施形態の多孔質中空糸濾過膜の好ましい膜構造を得るためには、内液中の有機成分である溶媒／非溶媒の比率を質量比でほぼ同量、例えば３５／６５〜６５／３５とし、有機成分／水の比率を質量比で７０／３０〜１００／０にすることが好ましい。It is preferable to use the same components as those used for the film-forming stock solution and the coagulation solution as the internal solution used during film formation. If NMP / TriEG, for example, is used as the solvent / non-solvent for the film-forming stock solution, and NMP / TriEG and water are used as the solvent / non-solvent for the coagulation solution, the internal solution is preferably composed of NMP / TriEG and water. .
Increasing the amount of solvent in the internal solution has the effect of slowing the progress of coagulation and slowing the formation of the film structure, while increasing the amount of non-solvent increases the viscosity of the solution, delaying the diffusion of the solution, and promoting the coagulation. Is effective in slowing the formation of the film structure and slowing the formation of the film structure.
In order to appropriately progress the coagulation, control the membrane structure, and obtain a preferable membrane structure of the porous hollow fiber filtration membrane of this embodiment, the ratio of the solvent / non-solvent that is an organic component in the internal liquid is set. It is preferable that the mass ratio is substantially the same, for example, 35/65 to 65/35, and the ratio of the organic component / water is 70/30 to 100/0 by mass ratio.
紡口温度は、適当な孔径とするために、４０〜６０℃が好ましい。
製膜原液は紡口から吐出された後、空走部を経て、凝固浴に導入される。空走部の滞留時間は０．０１〜０．７５秒が好ましく、０．０５〜０．４秒がより好ましい。滞留時間を０．０１秒以上とすることにより、凝固浴導入までの凝固を十分に進め、適当な孔径とすることができる。滞留時間を０．７５秒以下とすることにより、凝固の過度な進行を防ぎ、凝固浴での精密な膜構造制御を可能にする。The spinning temperature is preferably 40 to 60 ° C. in order to obtain an appropriate pore size.
After the film-forming stock solution is discharged from the spinning nozzle, it is introduced into the coagulation bath through the idle running portion. The residence time of the free running portion is preferably 0.01 to 0.75 seconds, and more preferably 0.05 to 0.4 seconds. By setting the residence time to 0.01 seconds or longer, solidification until the introduction of the coagulation bath can be sufficiently advanced to obtain an appropriate pore size. By setting the residence time to 0.75 seconds or less, excessive progress of coagulation is prevented, and precise membrane structure control in the coagulation bath is enabled.
ドラフト比は、紡糸工程での中空糸膜への延伸を制御するために、１．１〜６．０が好ましく、１．１〜４．０がより好ましい。ドラフト比とは、引取り速度と紡口からの製膜原液吐出線速度との比を意味する。
ドラフト比が高いとは、紡口から吐出されてからの延伸比が高いことを意味する。
一般的に、湿式相分離法で製膜されるとき、製膜原液が空走部を経て、凝固浴を出たときに、大方の膜構造が決定される。膜内部は、高分子鎖が絡み合うことにより形成される実部と高分子が存在しない空孔部となっている虚部から構成される。詳細な機構は不明であるが、凝固が完了する前に中空糸膜が過度に延伸されると、言い換えると、高分子鎖が絡み合う前に過度に延伸されると、高分子鎖の絡み合いが引き裂かれ、空孔部が連結されることにより、過度に大きな孔が形成されたり、空孔部が分割されることにより、過度に小さな孔が形成される。過度に大きな孔はウイルス漏れの原因となり、過度に小さな孔は目詰まりの原因となる。わずかな構造欠陥でも、ウイルス除去を目的とした膜においては、致命的となるため、ドラフト比は極力小さくすることが好ましい。The draft ratio is preferably 1.1 to 6.0 and more preferably 1.1 to 4.0 in order to control stretching to the hollow fiber membrane in the spinning process. The draft ratio means the ratio between the take-up speed and the film forming stock discharge linear speed from the spinning nozzle.
A high draft ratio means a high stretch ratio after being discharged from the spinning nozzle.
In general, when a film is formed by a wet phase separation method, most of the membrane structure is determined when the film-forming stock solution passes through an idle running portion and leaves the coagulation bath. The inside of the film is composed of a real part formed by entanglement of polymer chains and an imaginary part that is a void part in which no polymer exists. Although the detailed mechanism is unknown, if the hollow fiber membrane is excessively stretched before the solidification is completed, in other words, if the polymer chain is excessively stretched before the polymer chain is entangled, the entanglement of the polymer chain is torn. Then, by connecting the hole portions, an excessively large hole is formed, or by dividing the hole portion, an excessively small hole is formed. Excessively large pores cause virus leakage, and excessively small pores cause clogging. Even a slight structural defect is fatal in a film intended for virus removal, so it is preferable to make the draft ratio as small as possible.
製膜原液はフィルター、紡口を通り、空走部で適度に凝固された後、凝固液に導入される。凝固液に導入された製膜原液中の親水性高分子はポリスルホン系高分子の凝固に巻き込まれ、膜中に取り込まれるものと、ポリスルホン系高分子の凝固に巻き込まれず、凝固液中に拡散していくものがある。凝固液中に親水性高分子を添加することにより、製膜原液中と凝固液中の親水性高分子の濃度勾配を緩やかにすることで、この拡散速度を遅くさせ、中空糸膜の外表面側の親水性高分子の含有量を膜全体平均よりも多くすることが実現される。外表面の親水性高分子の含有率と膜全体の親水性高分子の含有率の比を１．２０〜１．６０にするためには、凝固液に添加する親水性高分子の量は、凝固液中２．０〜７．０質量％であることが分かった。 The film-forming stock solution passes through a filter and a spinneret, is appropriately solidified at the free running portion, and is then introduced into the coagulation liquid. The hydrophilic polymer in the film-forming stock solution introduced into the coagulation liquid is involved in the coagulation of the polysulfone polymer, and is incorporated into the membrane and is not involved in the coagulation of the polysulfone polymer, but diffuses into the coagulation liquid. There is something to go. By adding a hydrophilic polymer in the coagulation liquid, the diffusion gradient is slowed down by making the concentration gradient of the hydrophilic polymer in the membrane forming stock solution and the coagulation liquid gentle, and the outer surface of the hollow fiber membrane It is realized that the content of the hydrophilic polymer on the side is larger than the average of the entire film. In order to make the ratio of the content of the hydrophilic polymer on the outer surface and the content of the hydrophilic polymer on the entire membrane 1.20 to 1.60, the amount of the hydrophilic polymer added to the coagulation liquid is: It was found to be 2.0 to 7.0% by mass in the coagulation liquid.
凝固液は溶媒、非溶媒、水、及び親水性高分子から構成される。凝固液中の溶媒は凝固を遅らせる効果があり、水は凝固を早める効果があるため、凝固液組成は、溶媒／非溶媒は質量比で３５／６５〜６５／３５で、溶媒／水は質量比で７０／３０〜１０／９０が好ましい。溶媒／水の質量比の好ましい上限は、凝固を適切に進めて過度に大きな孔ができるのを防ぐ観点で設定される。好ましい下限は、凝固が早すぎて過度に小さな孔ができるのを防ぐ観点で設定される。
凝固浴温度は、孔径制御の観点で、３０〜６０℃が好ましい。The coagulation liquid is composed of a solvent, a non-solvent, water, and a hydrophilic polymer. Since the solvent in the coagulation liquid has the effect of delaying the coagulation, and water has the effect of accelerating the coagulation, the composition of the coagulation liquid is 35/65 to 65/35 in the mass ratio of solvent / non-solvent, The ratio is preferably 70/30 to 10/90. The preferable upper limit of the mass ratio of the solvent / water is set from the viewpoint of appropriately proceeding solidification and preventing formation of excessively large pores. The preferable lower limit is set from the viewpoint of preventing the formation of excessively small pores due to early solidification.
The coagulation bath temperature is preferably 30 to 60 ° C. from the viewpoint of controlling the pore diameter.
紡糸速度は、欠陥のない多孔質中空糸濾過膜が得られる条件であれば特に限定されないが、好ましくは５〜１５ｍ／ｍｉｎである。紡糸速度は生産性の観点で５ｍ／ｍｉｎ以上であることが好ましく、空走部の滞留時間の確保とドラフト比の適正化を可能にする観点で１５ｍ／ｍｉｎ以下であることが好ましい。 The spinning speed is not particularly limited as long as a porous hollow fiber filtration membrane having no defect is obtained, but is preferably 5 to 15 m / min. The spinning speed is preferably 5 m / min or more from the viewpoint of productivity, and is preferably 15 m / min or less from the viewpoint of ensuring the residence time of the idle running portion and optimizing the draft ratio.
凝固浴から引き上げられた中空糸膜は、水洗槽に導入されて温水で洗浄される。凝固浴から引き上げられた中空糸膜が水洗槽に導入されるまでの空中滞留時間を過度に長くなると、空中滞留中に外表面側からの中空糸の乾燥が過度に進行する。凝固浴中に親水性高分子が存在するため、凝固浴から出た中空糸膜の外表面近傍には、凝固浴に含まれる親水性高分子が存在する。中空糸外表面側の過度な乾燥を抑制し、外表面近傍の余分な親水性高分子を効率的に洗浄するため、凝固浴から水洗槽までの空中の滞留時間は１０秒未満とすることが好ましい。
温水での水洗工程では、溶媒と膜に固定化されていない親水性高分子を確実に除去することが好ましい。中空糸膜が溶媒を含んだまま乾燥されると、乾燥中に膜内で溶媒が濃縮され、ポリスルホン系高分子が溶解または膨潤することにより、膜構造を変化させる可能性があり、膜に固定化されていない親水性高分子が残存すると、孔を閉塞させ、膜の透過性を低下させる可能性がある。除去すべき溶媒及び非溶媒並びに膜に固定化されていない親水性高分子の拡散速度を高め、水洗効率を上げるため、温水の温度は５０℃以上が好ましい。水洗工程は、ネルソンローラを使用することが好ましい。十分に水洗を行うため、中空糸膜の水洗浴中の滞留時間は残存したＮＭＰにより、ウイルス除去膜として好ましくない膜構造に変化するのを防止する観点で８０秒以上が好ましく、不要成分の除去を目的とした水洗工程は長いほど好ましいが、生産効率の点から、３００秒以下とすることが適当である。The hollow fiber membrane pulled up from the coagulation bath is introduced into a washing tank and washed with warm water. If the air residence time until the hollow fiber membrane pulled up from the coagulation bath is introduced into the washing tank becomes excessively long, the drying of the hollow fiber from the outer surface side proceeds excessively during the air residence. Since the hydrophilic polymer is present in the coagulation bath, the hydrophilic polymer contained in the coagulation bath is present near the outer surface of the hollow fiber membrane exiting from the coagulation bath. In order to suppress excessive drying on the outer surface side of the hollow fiber and efficiently wash the excess hydrophilic polymer in the vicinity of the outer surface, the residence time in the air from the coagulation bath to the washing tank may be less than 10 seconds. preferable.
In the washing step with warm water, it is preferable to reliably remove the solvent and the hydrophilic polymer not immobilized on the membrane. If the hollow fiber membrane is dried while containing the solvent, the solvent is concentrated in the membrane during drying, and the polysulfone polymer may dissolve or swell, thereby changing the membrane structure and fixing to the membrane. If the hydrophilic polymer that has not been converted remains, the pores may be blocked and the permeability of the membrane may be reduced. The temperature of the hot water is preferably 50 ° C. or higher in order to increase the diffusion rate of the solvent and non-solvent to be removed and the hydrophilic polymer not immobilized on the membrane and increase the washing efficiency. The rinsing process preferably uses a Nelson roller. In order to sufficiently wash with water, the residence time in the washing bath of the hollow fiber membrane is preferably 80 seconds or more from the viewpoint of preventing the remaining NMP from changing to an unfavorable membrane structure as a virus removal membrane, and removal of unnecessary components The longer the water washing step for the purpose, the better. However, from the viewpoint of production efficiency, it is appropriate to set it to 300 seconds or less.
水洗浴から引き上げられた中空糸膜は、巻取り機でカセに巻き取られる。この時、中空糸膜を空気中で巻き取ると、膜は徐々に乾燥していき、わずかであるが、膜は収縮する。そして、巻取り初期と後期の膜の収縮度が異なり、膜構造が異なることとなり、生産工程において得られる中空糸膜の不均一性の原因となる。従って、中空糸膜は水中で巻き取られることが好ましい。 The hollow fiber membrane pulled up from the water washing bath is wound up on a cassette by a winder. At this time, when the hollow fiber membrane is wound up in the air, the membrane is gradually dried and slightly, but the membrane shrinks. And the shrinkage | contraction degree of the film | membrane of a winding initial stage and a late stage differs, and a membrane structure will differ, and it will cause the non-uniformity of the hollow fiber membrane obtained in a production process. Therefore, the hollow fiber membrane is preferably wound up in water.
カセに巻き取られた中空糸膜は、両端部を切断し、束にし、弛まないように支持体に把持させる。そして、把持された中空糸膜は、熱水中に浸漬、洗浄される。カセに巻き取られた状態の中空糸膜の中空部には、ナノメートルからマイクロメートルサイズのポリスルホン系高分子の微粒子が浮遊している白濁液が残存している。白濁液を除去せず、中空糸膜を乾燥させると、ポリスルホン系高分子の微粒子が中空糸膜の孔を塞ぎ、膜性能が低下するため、中空部内の白濁液を除去することが好ましい。
熱水処理工程では、中空糸膜の内表面側からも洗浄されるため、水洗工程で除去しきれなかった、膜に固定されなかった親水性高分子等が効率的に除去される。熱水の温度は５０〜１００℃が好ましい。熱水の温度は５０℃以上とすることが、洗浄効率を高くできる点で、好ましい。洗浄時間は３０〜１２０分が好ましい。熱水は洗浄中に数回、交換することが好ましい。The hollow fiber membrane wound around the cassette is cut at both ends to be bundled and held by the support so as not to loosen. The gripped hollow fiber membrane is immersed and washed in hot water. In the hollow portion of the hollow fiber membrane wound around the cake, a cloudy liquid in which fine particles of a polysulfone polymer having a nanometer to micrometer size are floating remains. If the hollow fiber membrane is dried without removing the white turbid liquid, it is preferable to remove the white turbid liquid in the hollow portion because the fine particles of the polysulfone-based polymer block the pores of the hollow fiber membrane and the membrane performance deteriorates.
In the hot water treatment process, since the inner surface side of the hollow fiber membrane is also washed, the hydrophilic polymer that has not been fixed in the membrane that could not be removed in the water washing step is efficiently removed. The temperature of hot water is preferably 50 to 100 ° C. The temperature of the hot water is preferably 50 ° C. or higher from the viewpoint of improving the cleaning efficiency. The washing time is preferably 30 to 120 minutes. The hot water is preferably changed several times during washing.
本実施形態において、巻き取られた中空糸膜は高圧熱水処理をすることが好ましい。具体的には、中空糸膜を完全に水に浸漬させた状態で、高圧蒸気滅菌機に入れ、１２０℃以上で２〜６時間処理するのが好ましい。詳細な機構は不明であるが、この高圧熱水処理により、中空糸膜中に微残存する溶媒及び非溶媒並びに膜に固着していない親水性高分子が完全に除去されるだけでなく、ポリスルホン系高分子と親水性高分子の存在状態が最適化され、本実施形態における多孔質中空糸濾過膜として好ましい構造が最適化されると考えられる。 In the present embodiment, the wound hollow fiber membrane is preferably subjected to high-pressure hot water treatment. Specifically, the hollow fiber membrane is preferably immersed in water and placed in a high-pressure steam sterilizer and treated at 120 ° C. or higher for 2 to 6 hours. Although the detailed mechanism is unknown, this high pressure hydrothermal treatment not only completely removes the solvent and non-solvent remaining in the hollow fiber membrane and the hydrophilic polymer not fixed to the membrane, but also polysulfone. It is considered that the existence state of the system polymer and the hydrophilic polymer is optimized, and a preferable structure as the porous hollow fiber filtration membrane in the present embodiment is optimized.
本実施形態の多孔質中空糸濾過膜は、風乾、減圧乾燥、又は熱風乾燥等により乾燥することにより得られる。特に限定されないが、乾燥中に膜が収縮しないように、中空糸膜の両端が固定された状態で、乾燥することが好ましい。 The porous hollow fiber filtration membrane of this embodiment is obtained by drying by air drying, reduced pressure drying, hot air drying or the like. Although not particularly limited, it is preferable to dry in a state where both ends of the hollow fiber membrane are fixed so that the membrane does not shrink during drying.
以下、実施例により本実施形態を詳細に説明するが、本発明は、以下の実施例に限定されるものではない。実施例における測定方法は以下のとおりである。 Hereinafter, although an embodiment explains this embodiment in detail, the present invention is not limited to the following examples. The measurement methods in the examples are as follows.
（１）内径及び膜厚の測定
多孔質中空糸濾過膜の内径は、膜の垂直割断面を実体顕微鏡で撮影することにより求めた。
内径と同様に外径を求め、（外径−内径）／２より膜厚を算出した。
また、膜面積として、内径×π×多孔質中空糸濾過膜の有効長とした。(1) Measurement of inner diameter and film thickness The inner diameter of the porous hollow fiber filtration membrane was determined by photographing a vertical section of the membrane with a stereomicroscope.
The outer diameter was obtained in the same manner as the inner diameter, and the film thickness was calculated from (outer diameter−inner diameter) / 2.
Further, the membrane area was defined as the effective length of inner diameter × π × porous hollow fiber filtration membrane.
（２）純水の透過速度の測定
１．０ｂａｒの定圧デッドエンド濾過による２５℃の純水の濾過量を測定し、濾過時間から透水量を測定して、純水の透過速度とした。(2) Measurement of pure water permeation rate The pure water permeation rate was measured from the filtration time by measuring the filtration amount of pure water at 25 ° C. by constant-pressure dead-end filtration at 1.0 bar.
（３）免疫グロブリンの濾過試験
多孔質中空糸濾過膜の本数が４本、有効長が８ｃｍになるように組み立てられたフィルターを１２２℃で６０分高圧滅菌処理をした。献血ヴェノグロブリンＩＨ ５％静注（２．５ｇ／５０ｍＬ）（田辺三菱製薬社製）を用いて、溶液の免疫グロブリン濃度が１．５質量％、塩化ナトリウム濃度が０．１Ｍ、ｐＨが４．５になるように溶液を調製した。調製した溶液をデッドエンドで、２．０ｂａｒの一定圧力で濾過を行った。濾過開始５分経過時の積算濾過量／５をＦ5とし、（２）において測定した透水量より、Ｆ5／Ｆwを算出した。(3) Immunoglobulin filtration test The filter assembled so that the number of porous hollow fiber filtration membranes was 4 and the effective length was 8 cm was subjected to high-pressure sterilization at 122 ° C for 60 minutes. Using blood donation Venoglobulin IH 5% IV (2.5 g / 50 mL) (manufactured by Mitsubishi Tanabe Pharma Corporation), the immunoglobulin concentration of the solution is 1.5 mass%, the sodium chloride concentration is 0.1 M, and the pH is 4. The solution was prepared to be 5. The prepared solution was filtered at a constant pressure of 2.0 bar with a dead end. F 5 / F w was calculated from the amount of water permeation measured in (2), where F 5 is the cumulative filtration rate at 5 minutes after the start of filtration.
（４）ブタパルボウイルスクリアランスの測定
（３）免疫グロブリンの濾過試験において調製した溶液に０．５容量％のＰＰＶ溶液をｓｐｉｋｅした溶液を濾過溶液とした。（３）免疫グロブリンの濾過試験と同様にして濾過試験を行った。濾液のＴｉｔｅｒ（ＴＣＩＤ50値）をウイルスアッセイにて測定した。ＰＰＶのウイルスクリアランスはＬＲＶ＝Ｌｏｇ（ＴＣＩＤ50）／ｍＬ（濾過溶液）−Ｌｏｇ（ＴＣＩＤ50）／ｍＬ（濾液）により算出した。(4) Measurement of porcine parvovirus clearance (3) A solution prepared by adding a spike of 0.5% by volume of a PPV solution to the solution prepared in the immunoglobulin filtration test was used as a filtration solution. (3) A filtration test was conducted in the same manner as the immunoglobulin filtration test. The titer (TCID 50 value) of the filtrate was measured by virus assay. The virus clearance of PPV was calculated by LRV = Log (TCID 50 ) / mL (filtrated solution) −Log (TCID 50 ) / mL (filtrate).
（５）緻密層の測定
中空糸膜断面を走査型電子顕微鏡（ＳＥＭ）により、撮影倍率を５０，０００倍、中空糸断面の膜厚方向に対して水平に視野を設定して撮影した。設定した一視野での撮影後、膜厚方向に対して水平に撮影視野を移動し、次の視野を撮影した。この撮影操作を繰り返し、隙間なく膜断面の写真を撮影し、得られた写真を結合して一枚の膜断面写真を得た。この断面写真において、（膜の円周方向に２μｍ）×（外表面から内表面側に向かって１μｍ）の範囲における平均孔径を算出し、外表面から内表面側に向かって１μｍ毎に膜断面の傾斜構造を数値化した。平均孔径は、以下のようにして算出した。ＭｅｄｉａＣｙｂｅｒｎｅｔｉｃｓ社製Ｉｍａｇｅｐｒｏ−ｐｌｕｓを用いて、明度を基準に空孔部と実部を識別し、識別できなかった部分やノイズをフリーハンドツールで補正し、空孔部の輪郭となるエッジ部分や、空孔部の奥に観察される多孔構造は空孔部として識別して、空孔部と実部の二値化処理を行った。二値化処理の後、空孔／１個の面積値を真円と仮定し、空孔の直径を算出した。視野の端部で途切れた空孔部についてもカウントして、全ての孔毎に実施し、２μｍ×１μｍの範囲毎に平均孔径を算出した。平均孔径が５０ｎｍ以下の範囲を緻密層と定義し、平均孔径が５０ｎｍ超の範囲を粗大層と定義した。(5) Measurement of dense layer The cross section of the hollow fiber membrane was photographed by a scanning electron microscope (SEM) with a photographing magnification of 50,000 times and a field of view set horizontally with respect to the film thickness direction of the hollow fiber cross section. After photographing with one set field of view, the field of view was moved horizontally with respect to the film thickness direction, and the next field of view was photographed. This photographing operation was repeated to photograph a film cross section without gaps, and the obtained photographs were combined to obtain a single film cross section photograph. In this cross-sectional photograph, the average pore diameter in the range of (2 μm in the circumferential direction of the membrane) × (1 μm from the outer surface to the inner surface side) is calculated, and the membrane cross section is taken every 1 μm from the outer surface to the inner surface side. The slant structure was quantified. The average pore diameter was calculated as follows. Using MediaPro-plus made by MediaCybernetics, the hole part and the real part are identified based on the brightness, the part and noise that could not be identified are corrected with a freehand tool, the edge part that becomes the outline of the hole part, The porous structure observed in the back of the hole part was identified as a hole part, and the binarization process of the hole part and the real part was performed. After the binarization treatment, the hole diameter was calculated on the assumption that the area value of holes / piece was a perfect circle. The pores that were interrupted at the edge of the field of view were also counted and implemented for every hole, and the average pore diameter was calculated for each range of 2 μm × 1 μm. A range having an average pore diameter of 50 nm or less was defined as a dense layer, and a range having an average pore diameter of more than 50 nm was defined as a coarse layer.
（６）緻密層の厚み
緻密層の厚みは、「平均孔径５０ｎｍ以下を示した範囲の数×１μｍ」として測定した。(6) Thickness of the dense layer The thickness of the dense layer was measured as “the number of ranges in which the average pore diameter was 50 nm or less × 1 μm”.
（７）膜中の親水性高分子の含有率及び外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比の測定
多孔質中空糸濾過膜を厚さ１０μｍで膜厚方向に切断した。切断した多孔質中空糸濾過膜断片を臭化カリウム板ではさみ、プレス機を用いて錠剤を成型した。錠剤としたものを顕微ＦＴ−ＩＲにより透過法で、５×５μｍを１セグメントとし、膜厚方向に連続的に測定した。測定したスペクトルよりポリスルホン系高分子由来のピークと親水性高分子由来のピークを検出し、親水性高分子由来のピークの吸光度面積／ポリスルホン系高分子由来のピークの吸光度面積比より、各分割したセグメントにおける親水性高分子の含有率として算出した。
各セグメントの親水性高分子の含有率の平均値を親水性高分子の膜中の含有率とした。
膜厚方向で最外表面側のセグメントの親水性高分子の含有率／親水性高分子の膜中の含有率を外表面の親水性高分子の含有率と膜中の親水性高分子の含有率の比として算出した。(7) Measurement of the ratio of the hydrophilic polymer content in the membrane and the ratio of the hydrophilic polymer content on the outer surface to the hydrophilic polymer content in the membrane A porous hollow fiber filtration membrane with a thickness of 10 μm Cut in the film thickness direction. The cut porous hollow fiber filtration membrane fragment was sandwiched between potassium bromide plates, and tablets were molded using a press. The tablet was measured by microscopic FT-IR using a transmission method, with 5 × 5 μm as one segment and continuously measured in the film thickness direction. A peak derived from a polysulfone polymer and a peak derived from a hydrophilic polymer were detected from the measured spectrum, and each peak was divided from the absorbance area ratio of the peak derived from the hydrophilic polymer / the peak derived from the polysulfone polymer. It calculated as the content rate of the hydrophilic polymer in a segment.
The average value of the content of the hydrophilic polymer in each segment was defined as the content of the hydrophilic polymer in the film.
The content of hydrophilic polymer in the segment on the outermost surface side in the film thickness direction / the content of hydrophilic polymer in the film, the content of hydrophilic polymer in the outer surface and the content of hydrophilic polymer in the film Calculated as the ratio of rates.
（実施例１）
ポリエーテルスルホン（ＰＥＳ）２７質量部（ＢＡＳＦ社製Ｕｌｔｒａｓｏｎ（商品名）Ｅ６０２０Ｐ）、ビニルピロリドンと酢酸ビニルの共重合体（ＢＡＳＦ社製Ｌｕｖｉｓｋｏｌ（登録商標）ＶＡ６４、以下、「ＶＡ６４」と記載する）９質量部、ＮＭＰ（キシダ化学社製）３０．４質量部、及びＴｒｉＥＧ（関東化学社製）３３．６質量部を５０℃で混合した後、減圧脱泡を７回繰り返した溶液を製膜原液とした。二重管ノズルの環状部から紡口温度は５０℃に設定して、製膜原液を吐出し、中心部からＮＭＰ４５．１質量部、ＴｒｉＥＧ４９．９質量部、及び水５質量部の混合液を内液として吐出した。
吐出された製膜原液と内液は、空走部を経て、３０℃、ＮＭＰ２６．８質量部、ＴｒｉＥＧ２９．６質量部、水３７．６質量部、及びＶＡ６４ ６質量部からなる凝固液を走行させた。凝固浴から引き出された中空糸膜は、５５℃に設定された水洗槽をネルソンロール走行させた後、水中で巻き取った。紡糸速度は８ｍ／ｍｉｎとし、ドラフト比は２とした。巻き取られた中空糸膜は両端を切断し、束にし、弛まないように支持体に把持させ、８０℃の熱水に浸漬させ、６０分間洗浄した。洗浄された中空糸膜は１２８℃、６時間の条件で、高圧熱水処理された後、真空乾燥して、多孔質中空糸濾過膜を得た。Example 1
Polyethersulfone (PES) 27 parts by mass (BASF Ultrason (trade name) E6020P), vinylpyrrolidone and vinyl acetate copolymer (BASF Luviskol (registered trademark) VA64, hereinafter referred to as “VA64”) After 9 parts by mass, 30.4 parts by mass of NMP (manufactured by Kishida Chemical Co., Ltd.), and 33.6 parts by mass of TriEG (manufactured by Kanto Chemical Co., Ltd.) were mixed at 50 ° C., a solution in which vacuum degassing was repeated seven times was formed into a film. The stock solution was used. The spinneret temperature is set to 50 ° C. from the annular part of the double-tube nozzle, the membrane forming stock solution is discharged, and a mixed liquid of NMP 45.1 parts by mass, TriEG 49.9 parts by mass and water 5 parts by mass from the center part. Discharged as internal solution.
The discharged film-forming stock solution and the internal solution pass through the idle running part, and run the coagulation liquid consisting of 30 ° C., NMP 26.8 parts by mass, TriEG 29.6 parts by mass, water 37.6 parts by mass, and VA64 6 parts by mass. I let you. The hollow fiber membrane pulled out from the coagulation bath was wound in water after running a Nelson roll in a water washing tank set at 55 ° C. The spinning speed was 8 m / min and the draft ratio was 2. The wound hollow fiber membrane was cut at both ends, bundled, held by a support so as not to loosen, immersed in hot water at 80 ° C., and washed for 60 minutes. The washed hollow fiber membrane was subjected to high-pressure hydrothermal treatment at 128 ° C. for 6 hours and then vacuum-dried to obtain a porous hollow fiber filtration membrane.
（実施例２）
凝固浴組成をＮＭＰ２７．４質量部、ＴｒｉＥＧ３０．２質量部、水３８．４質量部、及びＶＡ６４ ４質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。(Example 2)
A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1, except that the coagulation bath composition was changed to 27.4 parts by mass of NMP, 30.2 parts by mass of TriEG, 38.4 parts by mass of water, and 4 parts by mass of VA64.
（実施例３）
凝固浴組成をＮＭＰ２８．０質量部、ＴｒｉＥＧ３０．８質量部、水３９．２質量部、及びＶＡ６４ ２質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。Example 3
A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1 except that the coagulation bath composition was changed to NMP 28.0 parts by mass, TriEG 30.8 parts by mass, water 39.2 parts by mass, and VA64 2 parts by mass.
（実施例４）
凝固浴組成をＮＭＰ１８．６質量部、ＴｒｉＥＧ２０．６質量部、水５８．８質量部、及びＶＡ６４ ２質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。(Example 4)
A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1 except that the coagulation bath composition was changed to 18.6 parts by mass of NMP, 20.6 parts by mass of TriEG, 58.8 parts by mass of water, and 2 parts by mass of VA64.
（実施例５）
凝固浴組成をＮＭＰ９．３質量部、ＴｒｉＥＧ１０．３質量部、水７８．４質量部、及びＶＡ６４ ２質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。(Example 5)
A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1 except that the coagulation bath composition was changed to 9.3 parts by mass of NMP, 10.3 parts by mass of TriEG, 78.4 parts by mass of water, and 2 parts by mass of VA642.
（実施例６）
製膜原液組成をＰＥＳ２６質量部、ＶＡ６４ １０質量部、ＮＭＰ３２質量部、及びＴｒｉＥＧ３２質量部に変更した以外は実施例５と同様にして多孔質中空糸濾過膜を得た。(Example 6)
A porous hollow fiber filtration membrane was obtained in the same manner as in Example 5 except that the composition of the membrane forming stock solution was changed to 26 parts by mass of PES, 10 parts by mass of VA64, 32 parts by mass of NMP, and 32 parts by mass of TriEG.
（実施例７）
製膜原液組成をＰＥＳ２４質量部、ＶＡ６４ １２質量部、ＮＭＰ３０．４質量部、及びＴｒｉＥＧ３３．６質量部にし、凝固液組成をＮＭＰ３７．３質量部、ＴｒｉＥＧ２９．９質量部、水２８．８質量部、及びＶＡ６４ ４質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。(Example 7)
The composition of the film forming solution is 24 parts by mass of PES, 12 parts by mass of VA64, 30.4 parts by mass of NMP, and 33.6 parts by mass of TriEG, and the composition of the coagulation liquid is 37.3 parts by mass of NMP, 29.9 parts by mass of TriEG, and 28.8 parts by mass of water. A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1 except that VA64 was changed to 4 parts by mass.
（実施例８）
製膜原液組成をＰＥＳ３０質量部、ＶＡ６４ ６質量部、ＮＭＰ３０．４質量部、及びＴｒｉＥＧ３３．６質量部にし、凝固液組成をＮＭＰ２４．８質量部、ＴｒｉＥＧ２７．４質量部、水４２．８質量部、及びＶＡ６４ ５質量部に変更した以外は実施例１と同様にして多孔質中空糸濾過膜を得た。(Example 8)
The composition of the film forming stock solution is 30 parts by mass of PES, 6 parts by mass of VA64, 30.4 parts by mass of NMP, and 33.6 parts by mass of TriEG, and the composition of the coagulation liquid is 24.8 parts by mass of NMP, 27.4 parts by mass of TriEG, 42.8 parts by mass of water. A porous hollow fiber filtration membrane was obtained in the same manner as in Example 1 except for changing to 5 parts by mass of VA64.
実施例１〜８で得られた多孔質中空糸濾過膜について、（１）〜（７）について測定した結果を表１に示す。
実施例１〜８で得られた多孔質中空糸濾過膜はいずれも、濾過中の細孔表面へのタンパク質の吸着を抑制し、タンパク質透過性に優れていた。Table 1 shows the measurement results of (1) to (7) for the porous hollow fiber filtration membranes obtained in Examples 1 to 8.
All of the porous hollow fiber filtration membranes obtained in Examples 1 to 8 suppressed protein adsorption to the pore surface during filtration and were excellent in protein permeability.
（比較例１）
凝固液組成をＮＭＰ２６．２質量部、ＴｒｉＥＧ２９．０質量部、水３６．８質量部、及びＶＡ６４ ８質量部に変更した以外は実施例１と同様に中空糸膜を得た。(Comparative Example 1)
A hollow fiber membrane was obtained in the same manner as in Example 1 except that the coagulating liquid composition was changed to 26.2 parts by mass of NMP, 29.0 parts by mass of TriEG, 36.8 parts by mass of water, and 8 parts by mass of VA64.
比較例１で得られた中空糸膜について、（１）〜（７）について測定した結果を表１に示す。比較例１で得られた中空糸膜は、外表面の親水性高分子の含有率が高くなり、優れたタンパク質透過性を示さなかった。 Table 1 shows the measurement results of (1) to (7) for the hollow fiber membrane obtained in Comparative Example 1. The hollow fiber membrane obtained in Comparative Example 1 had a high content of hydrophilic polymer on the outer surface and did not show excellent protein permeability.
（比較例２）
凝固液組成をＮＭＰ２８．５質量部、ＴｒｉＥＧ３１．５質量部、及び水４０．０質量部に変更した以外は実施例１と同様に中空糸膜を得た。(Comparative Example 2)
A hollow fiber membrane was obtained in the same manner as in Example 1 except that the coagulating liquid composition was changed to 28.5 parts by mass of NMP, 31.5 parts by mass of TriEG, and 40.0 parts by mass of water.
比較例２で得られた中空糸膜について、（１）〜（７）について測定した結果を表１に示す。比較例２で得られた中空糸膜は、緻密層においてタンパク質の吸着を抑制することができず、優れたタンパク質透過性を示さなかった。 Table 1 shows the measurement results of (1) to (7) for the hollow fiber membrane obtained in Comparative Example 2. The hollow fiber membrane obtained in Comparative Example 2 could not suppress protein adsorption in the dense layer and did not show excellent protein permeability.
（比較例３）
凝固液組成をＮＭＰ３０．９質量部、ＴｒｉＥＧ３４．２質量部、水２７．９質量部、及びＶＡ６４ ７質量部に変更した以外は実施例７と同様に中空糸膜を得た。(Comparative Example 3)
A hollow fiber membrane was obtained in the same manner as in Example 7 except that the coagulating liquid composition was changed to 30.9 parts by mass of NMP, 34.2 parts by mass of TriEG, 27.9 parts by mass of water, and 7 parts by mass of VA64.
比較例３で得られた中空糸膜について、（１）〜（７）について測定した結果を表１に示す。比較例３で得られた中空糸膜は、親水性高分子の含有量が高くなり、緻密層の孔径が小さくなったため、優れたタンパク質透過性を示さなかった。 Table 1 shows the measurement results of (1) to (7) for the hollow fiber membrane obtained in Comparative Example 3. The hollow fiber membrane obtained in Comparative Example 3 did not show excellent protein permeability because the hydrophilic polymer content was high and the pore diameter of the dense layer was small.
（比較例４）
凝固液組成をＮＭＰ２５．６質量部、ＴｒｉＥＧ２８．３質量部、水４４．１質量部、及びＶＡ６４ ２質量部に変更した以外は実施例８と同様に中空糸膜を得た。(Comparative Example 4)
A hollow fiber membrane was obtained in the same manner as in Example 8 except that the coagulating liquid composition was changed to NMP 25.6 parts by mass, TriEG 28.3 parts by mass, water 44.1 parts by mass, and VA642 2 parts by mass.
比較例４で得られた中空糸膜について、（１）〜（７）について測定した結果を表１に示す。比較例４で得られた中空糸膜は、親水性高分子の含有量が低くなり、緻密層においてタンパク質の吸着を抑制することができず、優れたタンパク質透過性を示さなかった。 Table 1 shows the measurement results of (1) to (7) for the hollow fiber membrane obtained in Comparative Example 4. The hollow fiber membrane obtained in Comparative Example 4 had a low hydrophilic polymer content, could not suppress protein adsorption in the dense layer, and did not show excellent protein permeability.
本願は、２０１５年１月１９日に日本国特許庁に出願された日本特許出願（特願２０１５−８０５８）に基づくものであり、その内容はここに参照として取り込まれる。 This application is based on a Japanese patent application (Japanese Patent Application No. 2015-8058) filed with the Japan Patent Office on January 19, 2015, the contents of which are incorporated herein by reference.
本発明における多孔質中空糸濾過膜は、血漿分画製剤やバイオ医薬品の精製工程において産業上の利用可能性を有する。多孔質中空糸濾過膜は、タンパク質溶液に含まれるウイルスを除去し、タンパク質を回収するのに用いることができる。 The porous hollow fiber filtration membrane of the present invention has industrial applicability in the purification process of plasma fractionated preparations and biopharmaceuticals. The porous hollow fiber filtration membrane can be used to remove a virus contained in a protein solution and recover a protein.
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| JP6892874B2 (en) * | 2016-11-11 | 2021-06-23 | 富士フイルム株式会社 | Immune Isolation Membranes, Transplant Chambers, and Transplant Devices |
| EP3539575A4 (en) * | 2016-11-11 | 2019-11-13 | FUJIFILM Corporation | Immunoisolation membrane, transplantation chamber, and transplantation device |
| SG11201906766TA (en) * | 2017-02-17 | 2019-08-27 | Bayer Ag | Degassing in methods for continuous processing of a healthcare product |
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| JP2022117687A (en) | 2021-02-01 | 2022-08-12 | 三井・ケマーズ フロロプロダクツ株式会社 | Porous membrane prepared by stretching heat-treated sheet comprising polytetrafluoroethylene and/or modified polytetrafluoroethylene |
| CN113842792A (en) * | 2021-09-18 | 2021-12-28 | 杭州科百特过滤器材有限公司 | Asymmetric PES (polyether sulfone) filter membrane for virus removal and preparation method thereof |
| CN114452844B (en) * | 2022-01-29 | 2023-12-29 | 杭州科百特过滤器材有限公司 | PES hollow fiber membrane for purifying biomacromolecule, and preparation method and application thereof |
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|---|---|---|---|---|
| JP3279018B2 (en) * | 1993-11-12 | 2002-04-30 | エヌオーケー株式会社 | Method for producing porous membrane |
| CA2192351A1 (en) * | 1994-06-07 | 1995-12-14 | Akira Hajikano | Porous polysulfone membrane and process for producing the same |
| JP3314861B2 (en) * | 1996-12-24 | 2002-08-19 | 東洋紡績株式会社 | Hollow fiber membrane |
| EP1359995A4 (en) * | 2001-01-23 | 2004-04-07 | Innovasep Technology Corp | Asymmetric hollow fiber membranes |
| JP3594032B1 (en) * | 2003-08-29 | 2004-11-24 | 東洋紡績株式会社 | Highly permeable hollow fiber membrane blood purifier |
| JP3551971B1 (en) * | 2003-11-26 | 2004-08-11 | 東洋紡績株式会社 | Polysulfone permselective hollow fiber membrane |
| JP2005342139A (en) * | 2004-06-02 | 2005-12-15 | Toyobo Co Ltd | Polysulfone-based permselective hollow fiber membrane |
| US20070084788A1 (en) * | 2005-10-14 | 2007-04-19 | Millipore Corporation | Ultrafiltration membranes and methods of making and use of ultrafiltration membranes |
| WO2010035793A1 (en) * | 2008-09-26 | 2010-04-01 | 旭化成ケミカルズ株式会社 | Use of porous hollow-fiber membrane for producing clarified biomedical culture medium |
| KR20130014512A (en) * | 2010-03-09 | 2013-02-07 | 도요보 가부시키가이샤 | Porous, hollow fiber membrane for liquid treatment containing protein |
| JP6024660B2 (en) * | 2011-07-21 | 2016-11-16 | 東洋紡株式会社 | Porous hollow fiber membrane |
| JP2014015411A (en) * | 2012-07-06 | 2014-01-30 | Asahi Kasei Medical Co Ltd | Method for producing proteins |
| JP5403444B1 (en) * | 2012-11-15 | 2014-01-29 | 東洋紡株式会社 | Porous hollow fiber membrane |
-
2016
- 2016-01-19 WO PCT/JP2016/051458 patent/WO2016117565A1/en active Application Filing
- 2016-01-19 EP EP16740172.8A patent/EP3248672A4/en not_active Withdrawn
- 2016-01-19 US US15/544,342 patent/US20170348650A1/en not_active Abandoned
- 2016-01-19 JP JP2016570659A patent/JP6433513B2/en active Active
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| US20170348650A1 (en) | 2017-12-07 |
| WO2016117565A1 (en) | 2016-07-28 |
| EP3248672A4 (en) | 2018-01-10 |
| JPWO2016117565A1 (en) | 2017-09-28 |
| EP3248672A1 (en) | 2017-11-29 |
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